ARNT PROTEIN FUNCTION IN ANGIOGENESIS AND HEMATOPOIESIS

描述(逐字摘自研究人员摘要)：血管生成和 造血是与功能相关的过程，它产生血管和 循环系统的血细胞。最近的数据表明， 除发育调节信号外，缺氧(缺氧)， 是一种有效的血管生成和造血激活剂。为了调查 低氧调节这些过程的分子机制，突变有 在小鼠Arnt基因中产生，该基因编码bHLH-PAS转录 因素。Arnt蛋白调节EPO、VEGF等的表达 血管生成相关基因通过与其异源二聚体相互作用， HIF-1α。ARNT-/-ES细胞在低氧条件下未能上调可能的靶基因 条件，Arnt-/-突变胚胎在胚胎发育中停滞 E9.5-10.5天，显然是由于胎盘、卵黄中的血管异常 囊和胚胎本身。最近，有研究表明，ARNT-/- 突变还会扰乱卵黄囊血岛的正常造血。一个 第二，最近发现了高度相关的小鼠ArnT基因(Arnt2)。 虽然以与Arnt1显著不同的空间模式表达 在胚胎和成年小鼠中，Arnt2可能部分补偿了 Arnt-/-突变胚胎中Arnt蛋白的丢失。现建议： Arnt2-/-和Arnt2-/-，Arnt2-/-双突变小鼠的产生和分析 菌株，这将解决许多关于两者的作用的重要问题 ARNT和ArNT2在介导低氧诱导的血管生成和造血中的作用AS 低氧反应在各种病理中更为重要，包括 缺血后新生血管和肿瘤细胞凋亡的结果 实验应该被证明在开发临床方法方面有价值 未来。在基本层面上，它们将提供重要的信息。 低氧诱导的转录调控迅速补充我们的 扩大对受体/配体信号在血管生成和治疗中的作用的理解 造血术。

DESCRIPTION (Verbatim from investigator's abstract): Angiogenesis and hematopoiesis are functionally related processes that generate the vessels and blood cells of the circulatory system. Recent data have demonstrated that oxygen deprivation (hypoxia), in addition to developmentally regulated signals, is a potent activator of angiogenesis and hematopoiesis. To investigate the molecular mechanisms whereby hypoxia regulates these processes, mutations have been generated in the murine Arnt gene, which encodes a bHLH-PAS transcription factor. ARNT protein regulates the expression of Epo, VEGF and other angiogenesis-related genes through interactions with its heterodimeric partner, HIF-1alpha. Arnt -/- ES cells fail to upregulate may target genes under hypoxic conditions, and Arnt-/- mutant embryos are arrested in development at embryonic day E9.5-10.5, apparently due to vascular abnormalities in the placenta, yolk sac and embryo itself. More recently, it has been shown that the Arnt -/- mutation also disrupts normal hematopoiesis in yolk sac blood islands. A second, highly related murine Arnt gene (Arnt 2) has recently been described. Although expressed in a strikingly different spatial pattern than Arnt 1 in embryonic and adult mice, it is possible that Arnt 2 may partly compensate for the loss of the Arnt protein in Arnt -/- mutant embryos. It is proposed to generate and analyze Arnt 2 -/- and Arnt -/-, Arnt 2-/- double mutant mouse strains, which will address many important questions regarding the role of both Arnt and Arnt2 in mediating hypoxia-induced angiogenesis and hematopoiesis. As hypoxic responses are more important in a variety of pathologies, including post-ischemic neovascularization and tumor cell apoptosis, the results of these experiments should prove valuable in developing clinical approaches in the future. At a basic level, they will provide important information oon hypoxia-induced transcriptional regulation that complements our rapidly expanding understanding of receptor/ ligand signalling in angiogenesis and hematopoiesis.